Pharmacology and toxicology
Cholestyramine is an anion-cxchange resin which is not absorbed systemically. It binds bile acids, producing an insoluble complex which is excreted in the stool. This leads to a reduction of cholesterol and the low-density (LD) lipoproteins in the serum. Cholestyramine is used in pregnancy for the treatment of obstetric cholestasis to relieve the itching. Ursodeoxycholic acid is, however, more effective than cholestyramine in intrahepatic cholestasis of pregnancy (see ursodeoxycholic acid; Kondrackiene 2005). There is at least a theoretical risk for the fetus because, in addition to bile acids, cholestyramine also binds other lipophile substances - such as fat-soluble vitamins and medications. One case report concerning the gestational use of cholestyramine has described severe intracranial hemorrhage in a fetus; vitamin K deficiency was suspected (Sadler 1995).
Individual case studies argue against teratogenic properties (Landon 1987).
Other lipid reducers, such as acipimox, colestipol, i-sitosterin, eze-timibe xantinol and inositol nicotinate, and probucol, have not been sufficiently studied for pregnancy effects. Little systemic absorption of colestipol is believed to occur. As with the related agent cholestyra mine, colestipol can bind and impede the absorption of a variety of nutrients, including Lhe fat-soluble vitamins.
For these medications, too, there have not, as yet, been indications of specific teratogenic effects.
Recommendation. Cholestyramine - and, as a second choice, colestipol -may be used for intrahepatic cholestasis of pregnancy or when the use of a lipid reducer is strongly indicated. If used, sufficient supplementation of fat-soluble vitamins should be considered. These vitamins must be taken at a different time than the medication. Acipimox, i-sitosterin, ezetimibe, xantinol and inositol nicotinate, and probucol should not be used in pregnancy. However, their (inadvertent) use does not require either an interruption of the pregnancy or invasive diagnostic procedures.
Amfepramone (synonym diethylpropion), clobenzorex, dexfen-fluramine, fenfluramine, fenproporex, mazindol, mefenorex, norpseu-doephedrine, phentermine. and sibutramine are used as appetite suppressants. Amfepramone, clobenzorex, fenproporex, mefenorex, and phentermine share the pharmacological properties of amphetamines; dexfenfluraminc, fenfluramine, and sibutramine stimulate the release of serotonin and block its reuptake; norpseudoephedrine is a sympathomimetic amine; mazindol is a tricyclic drug structurally unrelated to amphetamine, but with the same actions as amphetamine.
Orlistat inhibits intestinal lipase and reduces fat absorption, which results in weight reduction.
Concerns about these medications have been repeatedly mentioned because of results in animal experiments and in connection with individual case studies. Bccause some of these drugs are vasoactive substances, it has been suggested that the perfusion-reducing effect could theoretically lead to vascular disruption-related birth defects.
A French collaborative study by Teratology Information Services, which evaluated 168 pregnancies primarily exposed to dexfenflu-ramine, did not provide any indication of teratogenic properties in this appetite suppressant (Vial 1992).
Pregnancy outcome in 98 prospectively ascertained pregnancies, exposed to the combination of fenfluramine and phentermine in early pregnancy, has been reported. No increased risk of malformations or other adverse effects was noted in this controlled study, although data are still insufficient for definitive conclusions (Jones 2002).
In two small case series, 11 live births (normal healthy babies) were reported after first-trimester exposure to sibutramine (Kadioglu 2004, Einarson 2004).
There is no or very limited experience with the use of mazindol or orlistat in pregnancy.
It has been hypothesized by other authors that disturbances in temperature regulation or ketoacidosis connected with weight loss could be responsible for embryotoxic damage such as. for instance, neural tube defects (Robert 1995, 1994).
Several publications discuss the association of maternal obesity and pregnancy complications, including birth defects (Scialli 2006). A preconceptionally existing maternal obesity is, according to a retrospective case-control study on 277 neural tube defect cases and controls, associated with at least a two-fold increased risk for neural tube defects, independent of periconceptional intake of folic acid and vitamins (Shaw 2000A). A prospective study evaluating 1451 children of obese mothers (Body mass index (BMI) a 30kg/m2) found an increased malformation rate (11.1%) with more than expected cases of encephalopathy, truncus arteriosus communis, and Potter sequence (Wiesel 2001). It is controversially discussed whether cardiovascular defects are more frequent among infants of obese mothers (Correa-Villasesor 2004). Another retrospective study observed significantly more obstructive renal anomalies in children of mothers with decreased fertility and a BMI a 25 kg/m2 (Honein 2003). Ceder-gen and co-workers (2005) report an increase of cleft lip/palate if maternal BMI is s29kg/m2. An impaired glucose metabolism or undiagnosed diabetes mellitus may be responsible for the observed increase of birth dcfects.
In another retrospective case-control study on 538 neural tube defect cases and 539 non-malformed controls, maternal lowered weight gain during pregnancy was associated with an increased risk of neural tube defects among offspring, especially when weight gain was less than 5 kg. The effect was independent of folic acid intake. According to Shaw and associates (2000B), it is not clear whether the lowered weight gain is cause of or caused by the neural tube defect. 'The same cases and controls were studied on dieting behaviors; the data suggest that restricted food intake during the first trimester may be associated with increased neural tube defect risk (Carmichael 2003).
Recommendation. Appetite suppressants are contra indicated during pregnancy. Accidental ingestion does not necessitate a termination of the pregnancy. In the case of abuse or long-term use during pregnancy, as well as after a considerable loss of weight in early pregnancy, a detailed fetal ultrasound is recommended to evaluate morphologic development; screening for neural tube defects using maternal serum or amniotic fluid (^-fetoprotein can be considered.
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